Abstract
The highly lethal Ebola virus species—Zaire (EBOV), Sudan (SUDV), and Bundibugyo (BDBV)—pose persistent threats to global health. Current antibody therapies target EBOV but lack broad neutralization across ebolaviruses. Recent pan-ebolavirus strategies rely on antibody cocktails. Here, we identified two camelid-derived nanobodies (1A10 and BA2) that neutralize EBOV, SUDV, and BDBV in vitro and protect female rodents against these pathogens. High-resolution cryo-EM structures of their GP complexes showed that 1A10 and BA2 bind conserved but non-overlapping epitopes near the GP1 base and GP2’s internal fusion loop (IFL), and biochemical analyses revealed their distinct neutralization mechanisms. To further improve efficacy, we engineered a bispecific antibody (BA2-1A10) via GS linker-mediated IgG-Fc fusion, which provided highly potent protection against all three viruses in female rodents model and positions it as a strong broad-spectrum anti-ebolavirus candidate. Our work demonstrates a structure-guided bispecific nanobody strategy for pan-ebolavirus therapy and highlights compact antibodies for next-generation antivirals.
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Data availability
Source data are provided as a Source Data file. All data needed to evaluate the conclusions in the paper are present in the paper or the Supplementary information. Atomic coordinates and structure factors for the reported cryo-EM structures have been deposited with the Protein Data Bank and Electron Microscopy Data Bank under accession numbers 9VTS/EMD-65343 (https://www.rcsb.org/structure/unreleased/9VTS; https://www.ebi.ac.uk/emdb/EMD-65343), 9VT4/EMD-65314 (https://www.rcsb.org/structure/unreleased/9VT4; https://www.ebi.ac.uk/emdb/EMD-65314). Other structures for analysis, including 5JQ3, 7M8L, 6PCI, and 7SWD were obtained from the PDB. No new sequencing data has been generated as part of in this study. Source data are provided with this paper.
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Acknowledgements
This work was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (Grant No. XDB0490000 to S.C., T.J., and P.G.), the National Key Research and Development Program (Grant No. 2022YFC2303300 to T.J. and P.G.), the National Natural Science Foundation of China (Grant No. 82302522 to M.W.), and the “USTC Research Funds of the Double First-Class Initiative (Grant No. YD9100002040). The funders had no role in the study design, data collection, and interpretation, or the decision to submit the work for publication. We thank Professor Huaju Chen for providing the original plasmids of EBOV-GPs. We thank Dr. Huan Ma, M.S Dongxiang Hong for helping with phage display library establish. We also thank Dr. Hengxia Jia for supporting the cryo-EM data collection and Dr. Bo Shu for helpful discussions in cryo-EM data proccessing and refinement. We thank the Institutional Center for Shared Technologies and Facilities of Wuhan Institute of Virology, Chinese Academy of Sciences, and the Cryo-EM Center at the University of Science and Technology of China for supporting cryo-EM data collection. We thank the National Biosafety Laboratory, Wuhan (CSTR: 31120.02.NBL), Chinese Academy of Sciences, for providing BSL-4 and ABSL-4 facility support for this project; the National Virus Resource Center; Experimental Animal Center, and Public Technology Service Center of Wuhan Institute of Virology, CAS, and the Animal Facility of USTC for their support.
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S.C. and T.C.J. conceived this study. S.C., T.C.J., P.G., M.H.W., and X.H.Z designed and directed the research; M.H.W, M.Y.L, J.H., and C.B.Y. immunized the camel, screened the Nbs, and analyzed sequences; M.H.W, M.Y.L., and Y.H.S. constructed the plasmids and produced antibodies; M.H.W performed the antibody characterization in vitro and engineering assay; L.X.Z and M.H.W performed the surface plasmon resonance (SPR) experiments; X.H.Z., E.T.L., M.H.W, C.P., B.Y.Z., and J.G.Z. performed the virus neutralization assay; M.H.W., Y.X.G., S.L.L., and Z.L.Z. performed the cryo-EM data collection, analysis, and deposition with the supervision of Tengchuan Jin (BA2 complex) and Peng Gong (1A10 complex). X.H.Z., Y.F.Y, W.J.L, F.X.L., M.Y.C., H.L., and F.H.Y. performed the rodents challenge studies; S.C., T.C.J, P.G., M.H.W., and X.H.Z. edited and revised the manuscript; all authors read and approved the paper.
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T.C.T., M.H.W., S.C., and E.T.L. are named inventors on two patents covering the sequences of the 1A10 and BA2 nanobodies described in this study. These patents pertain to the use of said nanobodies for the prevention, treatment, or diagnosis of Ebola virus infection and impose no restrictions on data publication. All other authors declare no competing interests.
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Wang, M., Zhang, X., Li, W. et al. A highly potent nanobody-based bispecific therapeutic provides broad-spectrum protection against ebolavirus. Nat Commun (2026). https://doi.org/10.1038/s41467-026-70464-6
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DOI: https://doi.org/10.1038/s41467-026-70464-6
